Type 2 diabetes is a type of lifestyle disease for which the number of patients with this disease has continued to increase in recent years. A prolonged hyperglycemic state gradually destroys microvessels throughout the body, resulting in the risk of causing serious damage to various organs including the oculus and kidney. These types of serious damage are referred to as diabetic complications, and among these, preventing the onset and inhibiting the progression of the three major diabetic complications consisting of diabetic neuropathy, diabetic retinopathy and diabetic nephropathy are becoming important issues.
Although the prevention of onset and inhibition of progression of diabetic complications are foremost based on the control of blood glucose level, increases in the activity of VAP-1 (vascular adhesion protein-1, also referred to as semicarbazide-sensitive amine oxidase (SSAO)) in blood and the correlation thereof with plasma glycosylated hemoglobin levels has been observed in diabetes patients in recent years. This enzyme, which is selectively located in vascular tissue, catalyzes deamination of methylamine and aminoacetone, respectively producing formaldehyde and methylglyoxal in addition to H2O2 and ammonia. Since each of these substances has cytotoxicity, increases in VAP-1 in blood are attracting attention as one of the causes of the onset of inflammatory diseases or diabetic complications (see, for example, Non-Patent Documents 1 and 2).
Various VAP-1 enzyme inhibitors have been reported thus far. A compound of the following formula:
is described to have VAP-1 inhibitory activity and being useful for the prevention and/or treatment of VAP-1-associated diseases including various types of inflammatory diseases and diabetic complications, and particularly diabetic nephropathy or diabetic macular edema (see, for example, Patent Document 1).
Moreover, a compound of the following formula:
is described to have VAP-1 inhibitory activity and being useful for the prevention and/or treatment of VAP-1-associated diseases including various types of inflammatory diseases and diabetic complications, and particularly diabetic nephropathy or diabetic macular edema (see, for example, Patent Document 2).
On the other hand, it has also been reported that expression of VAP-1 increases in the liver of patients with chronic liver disease, that soluble VAP-1 concentration in serum and expression of VAP-1 in the liver of patients with non-alcoholic fatty liver disease increase in comparison with that of patients not having non-alcoholic fatty liver disease, and that there is a correlation between soluble VAP-1 concentration in serum and the severity of fibrosis based on liver biopsies performed on patients with non-alcoholic fatty liver disease (see, for example, Non-Patent Document 3). On the basis thereof, in addition to the aforementioned diabetic complications, non-alcoholic fatty liver disease, and particularly non-alcoholic steatohepatitis, is expected to be prevented, alleviated and/or treated by inhibiting VAP-1.